8 results on '"Broide DH"'
Search Results
2. Prostaglandin I2 Signaling and Inhibition of Group 2 Innate Lymphoid Cell Responses.
- Author
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Zhou W, Toki S, Zhang J, Goleniewksa K, Newcomb DC, Cephus JY, Dulek DE, Bloodworth MH, Stier MT, Polosuhkin V, Gangula RD, Mallal SA, Broide DH, and Peebles RS Jr
- Subjects
- Alternaria immunology, Animals, Epoprostenol analogs & derivatives, Epoprostenol pharmacology, Humans, In Vitro Techniques, Interleukin-13 physiology, Interleukin-33 pharmacology, Interleukin-5 physiology, Lung cytology, Lung immunology, Lymphocytes drug effects, Mice, Mice, Inbred BALB C, Mice, Knockout, Signal Transduction drug effects, Epoprostenol physiology, Lymphocytes physiology, Signal Transduction physiology
- Abstract
Rationale: Group 2 innate lymphoid cells (ILC2s) robustly produce IL-5 and IL-13, cytokines central to the asthma phenotype; however, the effect of prostaglandin (PG) I2 on ILC2 function is unknown., Objectives: To determine the effect of PGI2 on mouse and human ILC2 cytokine expression in vitro and the effect of endogenous PGI2 and the PGI2 analog cicaprost on lung ILC2s in vivo., Methods: Flow-sorted bone marrow ILC2s of wild-type (WT) and PGI2 receptor-deficient (IP(-/-)) mice were cultured with IL-33 and treated with the PGI2 analog cicaprost. WT and IP(-/-) mice were challenged intranasally with Alternaria alternata extract for 4 consecutive days to induce ILC2 responses, and these were quantified. Prior to A. alternata extract, challenged WT mice were treated with cicaprost. Human flow-sorted peripheral blood ILC2s were cultured with IL-33 and IL-2 and treated with the PGI2 analog cicaprost., Measurement and Main Results: We demonstrate that PGI2 inhibits IL-5 and IL-13 protein expression by IL-33-stimulated ILC2s purified from mouse bone marrow in a manner that was dependent on signaling through the PGI2 receptor IP. In a mouse model of 4 consecutive days of airway challenge with an extract of A. alternata, a fungal aeroallergen associated with severe asthma exacerbations, endogenous PGI2 signaling significantly inhibited lung IL-5 and IL-13 protein expression, and reduced the number of lung IL-5- and IL-13-expressing ILC2s, as well as the mean fluorescence intensity of IL-5 and IL-13 staining. In addition, exogenous administration of a PGI2 analog inhibited Alternaria extract-induced lung IL-5 and IL-13 protein expression, and reduced the number of lung IL-5- and IL-13-expressing ILC2s and the mean fluorescence intensity of IL-5 and IL-13 staining. Finally, a PGI2 analog inhibited IL-5 and IL-13 expression by human ILC2s that were stimulated with IL-2 and IL-33., Conclusions: These results suggest that PGI2 may be a potential therapy to reduce the ILC2 response to protease-containing aeroallergens, such as Alternaria.
- Published
- 2016
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3. Immunostimulatory DNA inhibits transforming growth factor-beta expression and airway remodeling.
- Author
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Cho JY, Miller M, Baek KJ, Han JW, Nayar J, Rodriguez M, Lee SY, McElwain K, McElwain S, Raz E, and Broide DH
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- Animals, Bronchi anatomy & histology, Bronchi drug effects, Bronchial Hyperreactivity metabolism, Bronchial Provocation Tests, Bronchoalveolar Lavage Fluid chemistry, Bronchoalveolar Lavage Fluid cytology, Bronchoconstrictor Agents pharmacology, DNA genetics, Female, Humans, Inflammation metabolism, Interferon-gamma metabolism, Interleukin-5 metabolism, Methacholine Chloride pharmacology, Mice, Mice, Inbred BALB C, Muscle, Smooth cytology, Muscle, Smooth metabolism, Ovalbumin immunology, Respiratory System, Th2 Cells immunology, Bronchi immunology, Bronchi physiology, DNA immunology, Transforming Growth Factor beta metabolism
- Abstract
Immunostimulatory sequences of DNA (ISS) inhibit eosinophilic airway inflammation, Th2 responses, and airway hyperreactivity (AHR) in mouse models of acute ovalbumin (OVA)-induced airway inflammation. To determine whether ISS inhibits airway remodeling, we developed a mouse model of airway remodeling in which OVA-sensitized mice were repeatedly exposed to intranasal OVA administration for 1-6 mo. Mice chronically exposed to OVA developed sustained eosinophilic airway inflammation and sustained AHR to methacholine compared with control mice. In addition, the mice chronically exposed to OVA developed features of airway remodeling, including thickening of the peribronchial smooth muscle layer, peribronchial myofibroblast accumulation, expression of the profibrotic growth factor transforming growth factor-beta, and subepithelial collagen deposition (assessed by quantitation of the area of peribronchial trichrome staining using image analysis, and immunostaining with anti-collagen V antibodies). Administration of ISS systemically every other week significantly inhibited the development of AHR, eosinophilic inflammation, airway mucus production, and importantly, airway remodeling in mice chronically exposed to OVA for 3-6 mo. In addition, ISS significantly reduced bronchoalveolar lavage and lung levels of the profibrotic cytokine transforming growth factor-beta. These studies demonstrate that ISS prevents not only Th2-mediated airway inflammation in response to acute allergen challenge, but also airway remodeling associated with chronic allergen challenge.
- Published
- 2004
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4. Resolution of airway inflammation following ovalbumin inhalation: comparison of ISS DNA and corticosteroids.
- Author
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Ikeda RK, Nayar J, Cho JY, Miller M, Rodriguez M, Raz E, and Broide DH
- Subjects
- Administration, Inhalation, Adrenal Cortex Hormones adverse effects, Animals, Anti-Inflammatory Agents adverse effects, Anti-Inflammatory Agents therapeutic use, Apoptosis drug effects, Bronchial Hyperreactivity chemically induced, Bronchial Hyperreactivity pathology, Bronchial Hyperreactivity prevention & control, Bronchoalveolar Lavage Fluid chemistry, Bronchoalveolar Lavage Fluid cytology, DNA immunology, Dexamethasone adverse effects, Dexamethasone therapeutic use, Disease Models, Animal, Drug Therapy, Combination, Eosinophils metabolism, Eosinophils pathology, Female, Inflammation chemically induced, Injections, Intraperitoneal, Interferon-gamma drug effects, Interferon-gamma metabolism, Interleukin-5 metabolism, Lymph Nodes pathology, Lymphocytes drug effects, Mice, Mice, Inbred BALB C, Ovalbumin administration & dosage, Ovalbumin immunology, Pulmonary Eosinophilia chemically induced, Pulmonary Eosinophilia drug therapy, Pulmonary Eosinophilia pathology, Respiratory Hypersensitivity chemically induced, Treatment Outcome, Adrenal Cortex Hormones therapeutic use, DNA therapeutic use, Inflammation drug therapy, Ovalbumin adverse effects, Respiratory Hypersensitivity drug therapy
- Abstract
In this study we have compared the therapeutic effect of the administration of immunostimulatory DNA sequences (ISS) with that of corticosteroids on the resolution of airway inflammation and airway hyperreactivity (AHR) in a mouse model. Mice which had already developed significant levels of eosinophilic airway inflammation 24 h after allergen challenge were then treated with either ISS or corticosteroids, and the effect on AHR and airway inflammation assessed 6 d later. ISS inhibited AHR as effectively as corticosteroids. Combination therapy with ISS and corticosteroids was more effective than monotherapy with either ISS or corticosteroids in inhibiting AHR. In ovalbumin-challenged mice, levels of bronchoalveolar lavage (BAL) eosinophils were significantly reduced with either ISS or corticosteroids. ISS induced significant levels of BAL interferon-gamma, whereas corticosteroids did not induce expression of BAL interferon-gamma. Both ISS and corticosteroids significantly reduced levels of interleukin-5 in BAL, as well as the number of Periodic Acid Schiff-positive airway epithelial cells. Corticosteroids, but not ISS, increased the number of eosinophils in regional mediastinal lymph nodes. Very few apoptotic peribronchial cells were noted following ovalbumin challenge as assessed by TUNEL assay. Corticosteroids, but not ISS, induced an increase in the small number of apoptotic peribronchial cells. The mechanism by which either ISS or corticosteroids inhibit AHR is likely to be mediated by distinct and shared cellular pathways. The combination of the shared and distinct anti-inflammatory pathways may account for the additive effect of ISS and corticosteroids on inhibiting AHR.
- Published
- 2003
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5. Regulated production of the T helper 2-type T-cell chemoattractant TARC by human bronchial epithelial cells in vitro and in human lung xenografts.
- Author
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Berin MC, Eckmann L, Broide DH, and Kagnoff MF
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- Animals, Bronchoalveolar Lavage Fluid chemistry, Bronchoalveolar Lavage Fluid immunology, Cell Line, Transformed, Chemokine CCL17, Chemokines, CC analysis, Epithelial Cells cytology, Fetal Tissue Transplantation, Gene Expression Regulation, Neoplastic, Humans, In Vitro Techniques, Lung Neoplasms, Mice, Mice, Inbred C57BL, Mice, SCID, NF-kappa B genetics, RNA, Messenger analysis, Transplantation, Heterologous, Tumor Cells, Cultured, Bronchi cytology, Chemokines, CC genetics, Epithelial Cells immunology, Lung Transplantation immunology, Th2 Cells immunology
- Abstract
The chemokine TARC is a ligand for the chemokine receptor CCR4 expressed on T helper (Th)2-type CD4 T cells. Allergic airway inflammation is characterized by a local increase in cells secreting Th2-type cytokines. We hypothesized that bronchial epithelial cells may be a source of chemokines known to chemoattract Th2 cells. Regulated TARC expression was studied using normal human bronchial epithelial cells and a human lung xenograft model. TARC expression was increased in normal human bronchial epithelial cells in response to tumor necrosis factor-alpha stimulation, and further upregulation of TARC was observed with interferon (IFN)-gamma but not interleukin (IL)-4 costimulation. TARC functions as a nuclear factor (NF)-kappa B target gene, as shown by the abrogation of TARC expression in response to proinflammatory stimuli when NF-kappa B activation is inhibited. In an in vivo model, minimal constitutive TARC expression was observed in human lung xenografts. Consistent with our findings in vitro, TARC messenger RNA (mRNA) expression was upregulated in the xenografts in response to IL-1, and costimulation with IFN-gamma but not IL-4 further increased TARC mRNA and protein expression. In addition, bronchoalveolar lavage fluid from asthmatic subjects after allergen challenge contained significantly increased levels of TARC, suggesting that TARC production by bronchial epithelial cells may play a role in the pathogenesis of allergic asthma.
- Published
- 2001
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6. Inhibition of eosinophilic inflammation in allergen-challenged TNF receptor p55/p75--and TNF receptor p55-deficient mice.
- Author
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Broide DH, Stachnick G, Castaneda D, Nayar J, and Sriramarao P
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- Animals, Antigens, CD genetics, Bronchoalveolar Lavage Fluid cytology, Cell Adhesion, Disease Models, Animal, Endothelium, Vascular physiology, Inflammation genetics, Inflammation prevention & control, Interleukin-5 genetics, Interleukin-5 physiology, Lung immunology, Mice, Mice, Knockout, Mice, Transgenic, Microcirculation physiology, Ovalbumin immunology, Receptors, Tumor Necrosis Factor deficiency, Receptors, Tumor Necrosis Factor genetics, Receptors, Tumor Necrosis Factor, Type I, Receptors, Tumor Necrosis Factor, Type II, Splanchnic Circulation physiology, Tumor Necrosis Factor-alpha physiology, Allergens, Antigens, CD physiology, Eosinophils physiology, Inflammation immunology, Lung physiology, Methacholine Chloride pharmacology, Receptors, Tumor Necrosis Factor physiology
- Abstract
To determine the relative in vivo importance of tumor necrosis factor (TNF) release after allergen challenge to the subsequent endothelial adhesion and recruitment of eosinophils, we have compared eosinophil recruitment in TNF receptor p55/p75--deficient, TNF receptor p55--deficient, and control wild-type mice challenged with allergen. Bronchoalveolar lavage eosinophil recruitment in TNF receptor p55/p75--deficient and TNF receptor p55--deficient mice challenged with ovalbumin was significantly reduced compared with wild-type mice. To determine the mechanism of inhibition of eosinophil recruitment in TNF receptor-deficient mice, we used intravital microscopy to visualize the rolling and firm adhesion of fluorescently labeled mouse eosinophils in the microvasculature of the allergen-challenged mouse mesentery. Eosinophil rolling as well as eosinophil firm adhesion to endothelium were significantly inhibited in allergen-challenged TNF receptor p55/p75--deficient and TNF receptor p55--deficient mice compared with wild-type mice. Overall, these studies demonstrate that TNF, released after allergen challenge, is important in the induction of endothelial cell adhesiveness, a prerequisite for recruitment of circulating eosinophils.
- Published
- 2001
- Full Text
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7. Inhibition of pulmonary eosinophilia in P-selectin- and ICAM-1-deficient mice.
- Author
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Broide DH, Sullivan S, Gifford T, and Sriramarao P
- Subjects
- Animals, Antigens immunology, Chemotaxis, Leukocyte, Disease Models, Animal, Eosinophil Peroxidase, Eosinophils enzymology, Female, Hypersensitivity, Immediate, Intercellular Adhesion Molecule-1 genetics, Lung immunology, Mice, Mice, Mutant Strains, Ovalbumin immunology, P-Selectin genetics, Peroxidases analysis, Pulmonary Eosinophilia chemically induced, Skin immunology, Bronchoalveolar Lavage Fluid immunology, Intercellular Adhesion Molecule-1 immunology, P-Selectin immunology, Pulmonary Eosinophilia immunology
- Abstract
Adhesion molecule expression by pulmonary endothelial cells is considered to play an important role in the recruitment of circulating leukocytes to sites of inflammation in the lung. We have used P-selectin- and intercellular adhesion molecule type 1 (ICAM-1)-deficient mice to determine whether these adhesion molecules are important to pulmonary eosinophil recruitment after allergen challenge. There was a significant inhibition of lung tissue eosinophil recruitment in ICAM-1-deficient mice (approximately 84% inhibition compared to wild-type mice) and P-selectin-deficient mice (approximately 67% inhibition compared to wild-type mice) 3 h after allergen challenge. The number of bronchoalveolar lavage (BAL) eosinophils in P-selectin-deficient and ICAM-1-deficient mice was also significantly reduced compared with wild-type mice. Levels of BAL eosinophil peroxidase (EPO) were significantly lower in ICAM-1-deficient mice (0.21 +/- 0.03 EPO units) compared with wild-type mice (3.34 +/- 0.65 EPO units). There was no significant difference in the degree of inhibition of eosinophil recruitment in ICAM-1-deficient mice at the three time points (3, 12, and 24 h) of study after allergen challenge. However, in P-selectin-deficient mice there was a decline in the degree of inhibition of eosinophil recruitment from 3 h (67% inhibition) and 12 h (72% inhibition) postchallenge, to 24 h postchallenge (38% inhibition), suggesting that other adhesion molecules may be playing a more prominent role than P-selectin at later time points. These studies suggest an important role for ICAM-1 and P-selectin in eosinophil recruitment to the lung after allergen challenge.
- Published
- 1998
- Full Text
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8. Environmental and bronchoalveolar lavage Dermatophagoides pteronyssinus antigen levels in atopic asthmatics.
- Author
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Ferguson P and Broide DH
- Subjects
- Adult, Animals, Antigens, Dermatophagoides, Asthma etiology, Dust adverse effects, Environmental Exposure adverse effects, Environmental Exposure statistics & numerical data, Enzyme-Linked Immunosorbent Assay, Female, Glycoproteins administration & dosage, Humans, Hypersensitivity, Immediate etiology, Male, Nasal Lavage Fluid immunology, Statistics, Nonparametric, Antigens analysis, Asthma immunology, Bronchoalveolar Lavage Fluid immunology, Dust analysis, Environmental Exposure analysis, Glycoproteins analysis, Hypersensitivity, Immediate immunology, Mites immunology
- Abstract
Overnight environmental home exposure to Dermatophagoides pteronyssinus in IgE-sensitized individuals is often clinically associated with increased morning symptoms of rhinitis and/or asthma. We have investigated whether household exposure to D. pteronyssinus is associated with the presence of immunoreactive D. pteronyssinus I antigen (Der p I) in bronchoalveolar lavage (BAL) fluid in nine atopic asthmatics sensitized to D. pteronyssinus. Significant environmental concentrations of D. pteronyssinus were noted by light microscopy and immunoassay in the subjects' bedroom carpets (13.4 +/- 3.8 micrograms immunoreactive Der p I/g dust), mattresses (27.3 +/- 7.2 micrograms immunoreactive Der p I/g dust), and living room carpets (5.9 +/- 1.5 micrograms immunoreactive Der p I/g dust). Immunoreactive Der p I was measurable in 20-fold concentrated BAL fluids (3.4 +/- 1.0 ng/ml concentrated BAL fluid) after overnight home exposure. A 24-h hospitalization in a D. pteronyssinus controlled environment (< 0.02 micrograms Der p I/g dust) resulted in a significant decrease in BAL Der p I concentrations (0.8 +/- 0.6 ng/ml). In vivo studies in nine asthmatics challenged endobronchially with D. pteronyssinus (5-60 ng Der p I) induced significant airway eosinophilia. These studies demonstrate that environmental exposure to microgram amounts of D. pteronyssinus is associated with airway recovery of small nanogram amounts of Der p I.
- Published
- 1995
- Full Text
- View/download PDF
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